Department of Physiology, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.
Department of Physiology, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland; Center for Cognition, Learning and Memory, University of Bern, Fabrikstrasse 8, 3012 Bern, Switzerland.
Neuron. 2015 Apr 8;86(1):233-46. doi: 10.1016/j.neuron.2015.03.003. Epub 2015 Mar 26.
Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target.
神经病理性疼痛是由外周神经系统、脊髓和脊髓以上区域神经元功能的长期改变引起的。尽管人们认为大脑前区的功能变化有助于持续性疼痛的发展，但它们的意义和精确的亚细胞性质仍未被探索。通过对扣带前皮质神经元进行躯体和树突全细胞膜片钳记录，我们发现坐骨神经损伤导致 HCN 通道在第 5 层锥体神经元的树突中产生活性依赖性功能障碍，从而增强兴奋性突触后输入的整合并增加神经元放电。5-羟色胺受体 7 型（5-HT7R）的特异性激活通过增加 HCN 通道功能、恢复正常的树突整合以及减轻神经损伤动物的机械性疼痛过敏，缓解了损伤引起的病变。因此，在大脑前区水平的血清素能神经调节可以逆转神经病理性疼痛引起的树突功能障碍，可能代表一种潜在的治疗靶点。
